Clinical and Environmental Harmonization to Enhance Absorptive Predictability from Complex Dermal Products: In Vitro Permeation Testing to Healthy Volunteers
Abstract
Accurate establishment of in vitro-in vivo correlation (IVIVC) models for the bioavailability prediction of complex dermal products has been a challenge, leading to the use of multiple costly clinical studies for marketing approval. Although environmental conditions are highly controlled during in vitro permeation testing (IVPT), formulations such as lotions, gels, sprays and foams have historically generated variable absorptive profiles in vivo, making IVIVC mathematical modeling difficult. With no occlusive backing, dermal formulations undergo metamorphosis dependent upon environmental conditions, which are not typically precisely controlled during clinical testing. Since there are a wide range of formulations available on the market, sunscreens were selected as model products for translational evaluation. The goal of the present study was to examine multiple environmental and clinical factors in vitro that can alter absorption of the UV filter oxybenzone, and subsequently translate critical product testing conditions to a harmonized clinical protocol. Data from validated IVPT studies showed that temperature, dose and formulation were able to significantly alter the absorptive profile of oxybenzone. Therefore, a clinical study was designed utilizing four common dermal formulation types under un-occluded optimal dosing conditions with precise control of temperature and humidity during each procedure day. This human study data was then compared to prior sunscreen studies conducted by the US Food and Drug Administration (FDA), which did not include environmental controls during clinical assessment. The comparison showed that increased precision and harmonization between in vitro and in vivo methods for oxybenzone bioavailability assessment resulted in a decrease in variability associated with in vivo dermal product testing. Additionally, accurate IVIVC models for each formulation type tested were able to be generated. Models for in vivo exposure estimation of oxybenzone absorption from lotion, cream, solid stick and continuous spray sunscreen formulations were efficiently attained in a small number of healthy human volunteers with minimal dosage area required for predictable calculations of full body systemic exposure. This project lays the groundwork for effective pharmacokinetic (PK) safety and efficacy testing of other active pharmaceutical ingredients (API) absorbed from prescription and over-the-counter (OTC) complex dermal products.Description
University of Maryland, Baltimore. Pharmaceutical Sciences, Ph.D. 2021Keyword
In vitro permeation test (IVPT), In vitro/in vivo correlation (IVIVC), Oxybenzone, Pharmacokinetics (PK), Pharmacometrics, Sunscreenin vitro permeation test (IVPT)
in vitro/in vivo correlation (IVIVC)
oxybenzone
pharmacometrics
Pharmacokinetics
Sunscreening Agents
Identifier to cite or link to this item
http://hdl.handle.net/10713/17981Related items
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Evaluation of In Vitro/In Vivo Correlations for Transdermal Delivery Systems by In Vitro Permeation Testing and Human Pharmacokinetic Studies, With and Without a Transient Heat ApplicationAn in vitro model that exhibits in vitro/in vivo correlations (IVIVC) is a powerful tool in biopharmaceutical drug development because it can efficiently predict drug product performance in vivo. While the concept of IVIVC has been utilized mostly for oral dosage forms, demonstrations of IVIVC with in vitro permeation testing (IVPT) for transdermal delivery systems (TDS) are emerging. The objective of this work was to evaluate IVIVC for TDS using two model drugs, nicotine and fentanyl, with different physicochemical characteristics (e.g. log P). Additionally, the effect of heat exposure (42 ± 2 °C) on the rate and extent of TDS drug delivery was evaluated. IVPT studies using excised human skin and in vivo pharmacokinetic (PK) studies in human subjects were conducted under harmonized study conditions and designs to evaluate IVIVC. The correlations were evaluated in multiple ways, including a single point comparison of parameters such as steady-state concentration and heat-induced increase in partial AUCs, as well as a point-to-point correlation (Level A IVIVC). Level A IVIVC was examined using multiple approaches. A strong IVIVC was consistently observed for nicotine TDS in presence and absence of heat, suggesting the utility of IVPT as a tool to evaluate and predict in vivo performance of nicotine TDS. The IVIVC results for fentanyl were relatively weaker, especially when IVIVC for heat effects were examined, with greater in vivo heat effects observed compared to the in vitro heat effects. A separate study evaluating IVIVC for fentanyl TDS without a heat exposure component and utilization of some PK parameters obtained directly from study subjects yielded improved IVIVC results. The findings from the present research work suggest that IVPT data generally shows good predictability of in vivo performance of TDS at normal temperature conditions. However, the usefulness of IVPT for assessing and predicting external factors such as heat, especially for lipophilic drug molecules, may have some limitations that could be further improved.
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The development of an extended-release metoprolol tartrate dosage form, its in vitro and in vivo evaluation and the applications of in vitro-in vivo correlation across release mechanisms as a predictor of in vivo performanceIn the past four years three guidances have been prepared for the pharmaceutical industry which dealt with different aspects of extended-release dosage forms. This dissertation focused on one main issue from each of the three guidances. The first issue addressed pharmaceutical equivalence requirements. The second issue examined how multiple changes in formulation and process variables affect in vitro dissolution test result. The third issue concentrated on in vitro-in vivo correlation (IVIVC) as a predictor of in vivo performance across release mechanisms. A metoprolol tartrate extended-release capsule formulation was developed using fluid bed multiprocessor equipment with Wurster insert. Sugar spheres were drug-layered with metoprolol tartrate, seal-coated with Opadry (hydroxypropyl methylcellulose) and film-coated with Surelease (ethylcellulose). This dosage form was compared to a reference metoprolol tartrate matrix tablet dosage form which was formulated using Methocel K100LV (hydrodroxypropyl methylcellulose) as a hydrophilic polymer to retard the release. The mechanisms of release between both dosage forms differ. In the case of the tablet (reference) product, release is a function of the square root of time and the release rate can be controlled by the tablet porosity, addition of soluble solids, and the ratio of drug to carrier. The mechanism and kinetics of drug delivery from the capsule (test) formulation depend on the nature of the film and can be controlled by film porosity and thickness. For insoluble membranes made of ethylcellulose, drug release depends primarily on diffusion and partitioning of the drug into the membrane. Dissolution tests using different media, agitation speeds and methods were performed on both formulations to determine how the differences in dosage forms in terms of appearance or type (multiparticulate vs single unit) and release mechanism affect in vitro release. An in vitro-in vivo correlation (IVIVC) between plasma concentration and dissolution rate for matrix tablet formulation of the same drug was used to predict the in vivo performance of the capsule formulation. A clinical study was conducted using the capsule formulation and the bioavailability parameters derived from this study were compared to those predicted from the matrix tablet IVIVC. Both formulations released drug similarily under different dissolution testing conditions (f2>75). While the extent of release from both formulations was similar in vivo, the rate of release was not. This finding was also reflected in the predictions made using the matrix tablet IVIVC. The area under the curve (AUC) was adequately predicted (error<3%) whereas, the maximum concentration (Cmax) which is a bioavailability parameter that reflects rate in addition to extent of absorption was not well predicted(error>20%). The results demonstrate: (1) the f2 criteria used to determine in vitro profile similarity between formulations may not be suitable when the dosage forms being compared differ in release mechanisms, and/or (2) the IVIVC is formulation and mechanism dependent. The differences found in the in vivo absorption rates of these two formulations reflect differences in the dynamics of stomach emptying and intestinal transport between a multiparticulate dosage form compared to a monolithic matrix tablet dosage form.
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An in vitro model yields ‘importin’ new insights into chronic traumatic encephalopathy: damaged astrocytes stop ‘thrombospondin’ to the injury An Editorial Highlight for ‘Defective synthesis and release of astrocytic thrombospondin‐1 mediates the neuronal TDP‐43 proteinopathy, resulting in defects in neuronal integrity associated with chronic traumatic encephalopathy: in vitro studies’This Editorial highlights a study by Jayakumar and colleagues (2016) in the current issue of Journal of Neurochemistry. The authors introduce an in vitro model of chronic traumatic encephalopathy (CTE) to explore the mechanistic underpinnings of CTE pathogenesis, including investigation of how traumatized astrocytes affect traumatized neurons through the release of secreted factors. The model recapitulates two key features of the human post-mortem CTE brain: neuronal tauopathy and TDP-43 proteinopathy—the respective accretion of hyperphosphorylated tau and cytoplasmic hyperphosphorylated and ubiquitinated TDP-43. Oxidative stress and casein kinase 1 episilon (CK1ε) are identified as key upstream regulators of cytoplasmic TDP-43 phosphorylation, and this phosphorylation is found to correlate with decreased importin-β protein level and a decline in synaptic integrity. RNA silencing of importin-β is sufficient to mimic both the phospho-TDP-43 accumulation and synaptic injury observed after mild in vitro trauma. Strikingly, Jayakumar et al. find that thrombospondin-1 (TSP-1), a protein secreted by traumatized astrocytes at elevated levels during the initial 5 days after damage, can attenuate CK1ε phosphorylation of TDP-43 and synaptic injury. However, TSP-1 secretion by astrocytes is lost at 10–15 days post-injury, and neurons succumb to unchecked TDP-43 pathogenesis.
